Antibacterial lipo-random peptide mixtures exhibit high selectivity and synergistic interactions

Topman-Rakover, Shiri; Malach, Einav; Burdman, Saul; Hayouka, Zvi

doi:10.1039/d0cc04493h

Cited by 13 publications

(23 citation statements)

References 28 publications

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“…Before proceeding to evolution with combination of AMPs, the interaction between AMPs has been assessed. In order to evaluate these interactions, checkerboard assays were performed as previously described [40]. Briefly, hundred microliters of 5×10 5 CFU/ml log phase S. aureus cells were added into 96-well plates with different concentrations of two AMPs.…”

Section: Methodsmentioning

confidence: 99%

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Combination treatment can hinder the evolution of resistance to antimicrobial peptides

Maron

Friedman

Hayouka

2022

Preprint

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Antibiotic resistant microbial pathogens are becoming a major threat to human health. Therefore, there is an urgent need to develop new alternatives to conventional antibiotics. One such promising alternative is antimicrobial peptides (AMPs), which are produced by virtually all organisms and typically inhibit bacteria via membrane disruption. However, previous studies demonstrated that bacteria can rapidly develop AMP resistance. Here, we study whether combination therapy, known to be able to inhibit the evolution of resistance to conventional antibiotics, can also hinder the evolution of AMP resistance. To do so, we evolved the opportunistic pathogen S. aureus in the presence of individual AMP, AMP pairs, and a combinatorial antimicrobial peptide library. Treatment with some AMP pair indeed hindered the evolution of resistance compared with individual AMPs. In particular, resistance to pairs was delayed when resistance to the individual AMPs came at a cost of impaired bacterial growth, and did not confer cross-resistance to other tested AMPs. The lowest level of resistance evolved during treatment with the combinatorial antimicrobial peptide library termed random antimicrobial peptide mixture, which contains more than a million different peptides. A better understanding of how AMP combinations affect the evolution of resistance is a crucial step in order to design 'resistant proof' AMPs cocktails that will offer a sustainable treatment option for antibiotic resistant pathogens.

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Section: Methodsmentioning

confidence: 99%

“…MIC values were determined using a standard protocol [40]. Briefly, S. aureus cells were grown overnight in MH at 37 °C, 200 rpm.…”

Section: Methodsmentioning

confidence: 99%

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Combination treatment can hinder the evolution of resistance to antimicrobial peptides

Maron

Friedman

Hayouka

2022

Preprint

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“…RPMs were synthesized as previously described. − Previous publications have confirmed the success of the synthesis using MALDI-TOF mass spectrometry and amino acid analysis to validate the chain length of the synthesized peptide and that the 1:1 molar ratio of the two amino acids (phenylalanine and l / d -lysine) in FK20 or FdK RPMs was preserved during the synthesis. , The RPMs were dissolved in sterile deionized H 2 O to a concentration of 1 mg mL –1 , distributed into small aliquots, and stored at −20 °C. When used in experiments, aliquots were first thawed at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Random Peptide Mixtures as Safe and Effective Antimicrobials against Pseudomonas aeruginosa and MRSA in Mouse Models of Bacteremia and Pneumonia

Bennett

Kuo

et al. 2021

ACS Infect. Dis.

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Antibiotic resistance is a daunting challenge in modern medicine, and novel approaches that minimize the emergence of resistant pathogens are desperately needed. Antimicrobial peptides are newer therapeutics that attempt to do this; however, they fall short because of low to moderate antimicrobial activity, low protease stability, susceptibility to resistance development, and high cost of production. The recently developed random peptide mixtures (RPMs) are promising alternatives. RPMs are synthesized by incorporating a defined proportion of two amino acids at each coupling step rather than just one, making them highly variable but still defined in their overall composition, chain length, and stereochemistry. Because RPMs have extreme diversity, it is unlikely that bacteria would be capable of rapidly evolving resistance. However, their efficacy against pathogens in animal models of human infectious diseases remained uncharacterized. Here, we demonstrated that RPMs have strong safety and pharmacokinetic profiles. RPMs rapidly killed both Pseudomonas aeruginosa and Staphylococcus aureus efficiently and disrupted preformed biofilms by both pathogens. Importantly, RPMs were efficacious against both pathogens in mouse models of bacteremia and acute pneumonia. Our results demonstrate that RPMs are potent broad-spectrum therapeutics against antibiotic-resistant pathogens.

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“…Changes in the peptide moiety, such as substitution of amino acids or chemical modifications have produced alterations in their bioactivity [88] , [89] . Residues involved in hydrophobicity have been widely studied [88] , [90] , [91] , [92] , due to their role in membrane binding, insertion and destabilization processes [93] , [94] . For example, iturin A is a LP with antifungal activity [89] , with a methylation at the D-Tyr residue of iturin A resulting in increased bioactivity.…”

Section: Antimicrobial Role Of Lipopeptidesmentioning

confidence: 99%

The ecological roles of microbial lipopeptides: Where are we going?

Gutiérrez-Chávez

Benaud

Ferrari

2021

Computational and Structural Biotechnology Journal

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Lipopeptides (LPs) are secondary metabolites produced by a diversity of bacteria and fungi. Their unique chemical structure comprises both a peptide and a lipid moiety. LPs are of major biotechnological interest owing to their emulsification, antitumor, immunomodulatory, and antimicrobial activities. To date, these versatile compounds have been applied across multiple industries, from pharmaceuticals through to food processing, cosmetics, agriculture, heavy metal, and hydrocarbon bioremediation. The variety of LP structures and the diversity of the environments from which LP-producing microorganisms have been isolated suggest important functions in their natural environment. However, our understanding of the ecological role of LPs is limited. In this review, the mode of action and the role of LPs in motility, antimicrobial activity, heavy metals removal and biofilm formation are addressed. We include discussion on the need to characterise LPs from a diversity of microorganisms, with a focus on taxa inhabiting ‘extreme’ environments. We introduce the use of computational target fishing and molecular dynamics simulations as powerful tools to investigate the process of interaction between LPs and cell membranes. Together, these advances will provide new understanding of the mechanism of action of novel LPs, providing greater insights into the roles of LPs in the natural environment.

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Antibacterial lipo-random peptide mixtures exhibit high selectivity and synergistic interactions

Abstract: We report antimicrobial activity of 5-mer lipo-random peptide mixtures (lipo-RPMs) composed of l-Phe, d-Lys and palmitic acid. Synergistic interactions were detected between selected lipopeptides that compose the lipo-RPM mixture.

Cited by 13 publications

References 28 publications

Combination treatment can hinder the evolution of resistance to antimicrobial peptides

Combination treatment can hinder the evolution of resistance to antimicrobial peptides

Random Peptide Mixtures as Safe and Effective Antimicrobials against Pseudomonas aeruginosa and MRSA in Mouse Models of Bacteremia and Pneumonia

The ecological roles of microbial lipopeptides: Where are we going?

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